We have demonstrated the utility of the equine infectious anemia virus (EIAV)/Shetland pony system as a model for the natural immunologic control of a lentivirus infection and for the evaluation of lentivirus vacc e strategies. The results of experimental infection studies have indicated fo the first time that the evolution of protective immunity during persistent infection in ponies is a complex and lengthy process over at least a 6-8 month period that involves substantial changes in virus specific immune responses. However, reliable immune correlates of protection remain undefined. The results obtained with experimental EIAV vaccines based on inactivated whole virus, viral envelope subunits, and baculovirus recombinant envelope proteins revealed a remarkable range of efficacy, ranging from sterile protection to severe enhancement of virus replication and disease in immunized ponies inoculated with standard challenge strains of EIAV. These experiments indicate that immune responses to EIAV are a double-edged sword that can mediate protection or enhancement. Thus, the EIAV system provides a unique lentivirus model in which to characterize the nature of immune responses associated with protective and enhancing immune responses, to define the viral determinants of protection and enhancement, and to evaluate and test vaccine strategies that maximize protective and minimize enhancing immune responses. Our observations with EIAV (and SIV) have led to the central hypothesis that extended immune maturation of virus-specific immune responses is a prerequisite to the development of immunological control of a lentivirus infection, and that effective vaccines must achieve this mature immune status to protect against virus infection. Thus, we propose here to extend our immunologic studies: (I) to characterize the immunogenic determinants of EIAV proteins and to determine the relevance of antigenic variation to viral persistence, (2) to examine in detail the evolution of virus-specific immune responses in experimentally infected ponies, (3) to characterize immune responses associated with vaccine protection and enhancement, and (4) to evaluate selected immunogens and vaccination strategies for their ability to elicit protective immunity. It is anticipated that the results of these EIAV immunology studies will provide fundamental new information that will be relevant to the design and evaluation of candidate AIDS vaccines.